Mice With Hyperghrelinemia Are Hyperphagic and Glucose Intolerant and Have Reduced Leptin Sensitivity

Department of Investigative Medicine, Hammersmith Campus, Imperial College London, London, UK.
Diabetes (Impact Factor: 8.47). 02/2009; 58(4):840-6. DOI: 10.2337/db08-1428
Source: PubMed

ABSTRACT Ghrelin is the only known peripheral hormone to increase ingestive behavior. However, its role in the physiological regulation of energy homeostasis is unclear because deletion of ghrelin or its receptor does not alter food intake or body weight in mice fed a normal chow diet. We hypothesized that overexpression of ghrelin in its physiological tissues would increase food intake and body weight.
We used bacterial artificial chromosome transgenesis to generate a mouse model with increased ghrelin expression and production in the stomach and brain. We investigated the effect of ghrelin overexpression on food intake and body weight. We also measured energy expenditure and determined glucose tolerance, glucose stimulated insulin release, and peripheral insulin sensitivity.
Ghrelin transgenic (Tg) mice exhibited increased circulating bioactive ghrelin, which was associated with hyperphagia, increased energy expenditure, glucose intolerance, decreased glucose stimulated insulin secretion, and reduced leptin sensitivity.
This is the first report of a Tg approach suggesting that ghrelin regulates appetite under normal feeding conditions and provides evidence that ghrelin plays a fundamental role in regulating beta-cell function.

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Available from: Michael Patterson, Jan 28, 2014
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    • "However other laboratories generated Tg mice with increased AG levels. AG or ghrelin analog over-expression exhibited late onset impaired glucose homeostasis despite no changes in body weight [8] [24] [44] [66]. Due to the difficulties to obtain models with high AG levels, some groups developed Tg mice to over-express ghrelin using different strategies. "
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    • "To further complicate the manner in which we view the integrated control of food intake and body weight by ghrelin and leptin, a transgenic model of bioactive ghrelin overexpression demonstrates reduced sensitivity to the anorectic actions of leptin (Bewick et al., 2009). However, ablation of ghrelin in leptin-deficient ob/ob mice fails to reduce the obese hyperphagic phenotype of the ob/ob mice, although it does markedly improve the hyperglycemic phenotype of the ob/ob mice (Sun et al., 2006). "
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